DESCRIPTION: The major cause of heart failure is the regional loss of myocardium following myocardial infarction. Because the loss of tissue is highly localized, and the endogenous response is not sufficient for repair, recent efforts have focused on the prevention of initial cell death using a variety of treatment options. Inhibition of p38 activation has been associated with improved function following myocardial infarction, however the size of the inhibitor makes it difficult to sustain in larger animals. The objective of this proposal is to encapsulate SB239063, a potent inhibitor of p38 phosphorylation, within polyketal particles to enhance myocardial retention and improve function following infarction. In vivo inhibitor studies and dominant negative mouse approaches demonstrate a clear potential of p38 inhibition to treat cardiac dysfunction following myocardial infarction;however the relatively small size of the inhibitor has limited its use in larger animal studies. Polyketal particles are a new class of polymers that are stable, degrade in to FDA-approved compounds, can be modified easily and can encapsulate proteins while retaining activity. The central hypothesis of this proposal is that polyketal particles encapsulate this p38 inhibitor and block apoptosis of cardiac myocytes, as well as prevent stimulated cytokine release from macrophages both in vitro and in vivo following myocardial infarction. We also believe this effect will extend to endogenous cardiac stem cells, in addition to serving a protective role for implanted stem cells as well. The successful completion of this R01 proposal will demonstrate that polyketal particles loaded with this small molecule inhibitor can be used to treat cardiac dysfunction following myocardial infarction. We further believe completion of this proposal will also demonstrate a role for polyketal-encapsulated p38 inhibition as an adjunct therapy for cell transplantation. Given the complicated endogenous response following myocardial infarction, we believe that data from this proposal will generate widespread interest in using polyketals for myocardial drug delivery. PUBLIC HEALTH RELEVANCE: Congestive heart failure is a leading cause of morbidity and mortality worldwide and effective treatment options are greatly needed. We propose to encapsulate and deliver SB239063, a potent p38 inhibitor with therapeutic potential, directly to the myocardium using a new class of polymers called polyketals. This proposal will demonstrate that p38 inhibition with polyketals can be used to help regenerate cardiac tissue following myocardial infarction.